This invention relates to novel 4-(2-keto-1-benzimidazolinyl)piperidine compounds or their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their medical uses. The compounds of this invention have activity as ORL1-receptor (opioid receptor-like 1 receptor) agonists, and as such are useful as an analgesic, anti-inflammatory, diuretic, anesthetic, neuroprotective, anti-hypertensive, or an anti-anxiety agent, or as an agent for appetite control or hearing regulation.
In spite of their usefulness as analgesics, usage of opioids such as morphine and heroin are strictly limited. This is because these drugs induce side effects such as euphoria or respiratory failure. Further, multiple dosage of the drugs cause addiction. Thus, there has been a long-felt need to provide less toxic analgesics.
Considerable pharmacological and biochemical studies have been carried out to identify opioid receptors and their endogenous ligands, and peptide and non-peptide opioid ligands have been discovered. In the recent past, amino acid sequences of xcexc-, xcex4- and xcexa-opioid receptor subtypes have been identified and reported. Subsequently, a novel receptor subtype was identified and termed ORL1-receptor, and Meunier, J.-C et al., reported the isolation and structure of the endogenous agonist of the receptor (Nature, Vol. 377, pp. 532-535, Oct. 12, 1995). It is suggested that the agonist for ORL1-receptor be effective in neurogenic inflammation (Tips, Vol. 18, pp. 293-300, August 1997). It is also suggested that the agonist be a potent analgesic having less psychological side effects and addiction (D. Julius, Nature, Vol. 377, p. 476, Oct. 12, 1995).
WO 97/40035 and U.S. Pat. No. 3,318,900 disclose a series of benzimidazolinyl piperidines.
The present invention provides a compound of the following formula: 
or the pharmaceutically acceptable salts thereof, wherein
R1 and R2 are independently C1-C4 alkyl; or
R1 and R2, taken together with the carbon atom to which they are attached, form a mono-, bi-, tri- or spiro-cyclig group having 6 to 13 carbon atoms, wherein the cyclic group is optionally substituted by one to five substituents independently selected from C1-C4 alkyl, C2-C4 alkylene, C1-C4 alkoxy, hydroxy, oxo, xe2x95x90CH2 and xe2x95x90CHxe2x80x94C1-C4 and alkyl;
R3 is C1-C7 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, phenyl-C1-C5 alkyl, phenyl optionally substituted by one to three substituents independently selected from fluorine, C1-C3 alkyl and C1-C3 alkoxy, or a heteroaryl group selected from furyl, thienyl, pyrrolyl and pyridyl, wherein said heteroaryl group is optionally substituted by one to three substituents independently selected from halo, C1-C3 alkyl and C1-C3 alkoxy, with the proviso that when both R1 and R2 are C1-C4 alkyl, then R3 is other than C1-C7 alkyl, C2-C5 alkenyl and C2-C5 alkynyl;
R4 is selected from:
1) hydrogen,
2) optionally mono- or di-substituted, C1-C8 alkyl, C3-C7 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C6 alkyl-Zxe2x80x94, C1-C6 alkyl-Zxe2x80x94(C1-C6)alkyl, C3-C7 cycloalkyl-Zxe2x80x94(C1-C6)alkyl, C2-C6 alkenyl-Zxe2x80x94(C1-C6)alkyl or C2-C6 alkynyl-Zxe2x80x94(C1-C6)alkyl, wherein Z is selected from O, S, SO, SO2, CO, CO2, OCO, NR, CONR and NRCO, wherein R is hydrogen or C1-C6 alkyl, and the substituents to be attached to the alkyl, alkenyl, alkynyl or cycloalkyl moiety are independently selected from halo, hydroxy, carboxy, amino, mono- or di-(C1-C4 alkyl)amino, hydrazino, azido, ureido, amidino and guanidino; or
3) optionally mono- or di-substituted, aryl, heterocyclic, aryl(C1-C5)alkyl, heterocyclic(C1-C5)alkyl, heterocyclic-heterocyclic(C1-C5)alkyl, aryl-heterocyclic(C1-C5)alkyl, heterocyclic-Zxe2x80x94(C1-C5)alkyl, aryl-Zxe2x80x94(C1-C5)alkyl, aryl(C1-C5 )alkyl-Zxe2x80x94(C1C5 )alkyl, or heterocyclic(C1-C5 )alkyl-Zxe2x80x94(C1-C5)alkyl, wherein Z is selected from O, S, SO, SO2, CO, CO2, OCO, NR, CONR and NRCO, wherein R is hydrogen or C1-C6 alkyl, and the substituents to be attached to the aryl or heterocyclic moiety are independently selected from halo, hydroxy, carboxy, C1-C4 alkyl, halo C1-C4alkyl, C1-C4 alkoxy, C1-C4 alkyl-COxe2x80x94, amino(C1-C4)alkyl-COxe2x80x94, phenyl, benzyl, amino, mono- or di-(C1-C4 alkyl)amino, hydrazino, azido, ureido, amidino and guanidino;
R5 is independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylsulfonyl, CF3, carboxy, hydroxy, amino, alkylamino, acylamino, arylcarbonyl, alkylcarbonyl and hydroxyalkyl; and
n is 0, 1, 2, 3 or 4.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term xe2x80x9calkoxy xe2x80x9d, as used herein, includes O-alkyl groups wherein xe2x80x9calkylxe2x80x9d is defined above.
The term xe2x80x9chaloxe2x80x9d, as used herein, refers to F, Cl, Br or I, preferably F or Cl.
The term xe2x80x9cC2-C4 alkylenexe2x80x9d means a straight or branched radical formed from an unsaturated aliphatic hydrocarbon such as ethenyl, propenyl or butenyl.
The term xe2x80x9ccycloalkylxe2x80x9d, as used herein, means a saturated carbocyclic radical including, but not limited to, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
The term xe2x80x9carylxe2x80x9d, as used herein, means a monocyclic or bicyclic aromatic carbocyclic ring system of 6-11 carbon atoms including, but not limited to, phenyl, naphthyl, indanyl, (1,2,3,4)-tetrahydronaphthyl, indenyl, isoindenyl and the like.
The term xe2x80x9cheterocyclicxe2x80x9d means a monocyclic or bicyclic hydrocarbon ring system which has one or more hetero atoms in the ring, preferably has 4 to 10 carbon atoms and 1 to 3 heteroatoms including, but not limited to, piperidino, hexamethyleneimino, morpholino, thiamorpholino, pyrrolidino, pyrazolino, pyrazolidino, pyrazoryl, piperazinyl, furyl, thienyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinolyl, thiophenyl, pyrazinyl, pyridazinyl, aziridinyl and azetidinyl.
The term xe2x80x9cbi- or tri-cyclic ringxe2x80x9d means hydrocarbon cyclic groups of 6 to 16 carbon atoms, having two to three rings therein, including, but not limited to, decahydronaphthalene, bicyclo[2.2.1.]heptane, bicyclo[3.2.1]octane, bicyclo[3.3.1]nonane, adamantane and tricyclo[5.2.1.02,6]decane.
The term xe2x80x9cspirocyclic groupxe2x80x9d means a hydrocarbon spirocyclic group of 6 to 13 carbon atoms, including, but not limited to, spiro[5.5]undecanyl and spiro[4.5]decanyl.
The term xe2x80x9ctreatingxe2x80x9d, as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term xe2x80x9ctreatmentxe2x80x9d as used herein refers to the act of treating, as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
A preferred group of the compounds of the present invention includes the compound of Formula (I), wherein
R1 and R2 are independently C1-C4 alkyl; or
R1 and R2, taken together with the carbon atom to which they are attached, form a monocyclic group selected from cyclo-C3-C14 alkyl and cyclo-C4-C14 alkenyl, a bicyclic group selected from decahydronaphthalene, bicyclo[2.2.1.]heptane, bicyclo[4.3.0]nonane, bicyclo[3.2.1]octane, bicyclo[3.2.0]heptene and bicyclo[3.3.1]nonane, a tricyclic group selected from adamantane and tricyclo[5.2.1.02.6]decane, or a spirocyclic group selected from spiro[5.5]undecanyl and spiro[4.5]decanyl, wherein the cyclic group is optionally substituted by one to three substituents independently selected from C1-C4 alkyl, C2-C4 alkylene, C1-C4 alkoxy, hydroxy and oxo;
R3 is C1-C7 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, phenyl-C1-C5 alkyl, phenyl optionally substituted by one to three substituents independently selected from fluorine, C1-C3 alkyl and C1-C3 alkoxy, or thienyl;
R4 is selected from:
1) hydrogen;
2) optionally mono- or di-substituted, C1-C8 alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C1-C6 alkyl-Zxe2x80x94(C1-C6)alkyl, C3-C7 cycloalkyl-Zxe2x80x94(C1-C6)alkyl or C2-C6 alkenyl-Zxe2x80x94(C1-C6)alkyl, wherein Z is selected from NH, O, S, SO, SO2, CO, CO2, OCO, CONH and NHCO, and the substituents are independently selected from halo, hydroxy, amino, mono- or di-(C1-C4 alkyl)amino, hydrazino, azido, ureido, amidino and guanidino; or
3) optionally mono- or di-substituted, aryl, heterocyclic, aryl(C1-C5)alkyl, heterocyclic(C1 -C5)alkyl, heterocyclic-piperazino(C1-C5)alkyl, heterocyclic-amino(C1-C5)alkyl, heterocyclic-Zxe2x80x94(C1-C5)alkyl, aryl-Zxe2x80x94(C4-C5)alkyl, aryl(C1-C5)alkyl-Zxe2x80x94(C1-C5)alkyl or heterocyclic(C1-C5)alkyl-Zxe2x80x94(C1-C5)alkyl, wherein the aryl group is selected from phenyl and naphthyl, and the heterocyclic group is selected from furyl, thiophenyl, pyridyl, pyrimidiny, pyrazinyl, pyridazinyl, aziridinyl, azethidinyl, pyrrolidinyl, piperidino, hexamethyleneimino, piperazino and morpholino;
Z is selected from NH, O, S, SO, SO2,CO, CO2, OCO, CONH and NHCO; and
the substituents are independently selected from halo, hydroxy, carboxy, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkyl-COxe2x80x94, phenyl, benzyl, amino, mono- or di-(C1-C4 alkyl)amino, hydrazino, azido, ureido, amidino and guanidino; and
R5 is halo, CF3 or C1-C3 alkoxy; and
n is 0, 1, 2or 3.
A more preferred group of this invention includes the compounds of Formula (I), wherein R1 and R2, taken together with the carbon atom to which they are attached, form a cyclic group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cycloheptenyl, dimethylcyclohexyl, butylcyclohexyl, isopropylidenecyclohexyl, bicyclo[4.3.0]nonanyl and spiro[5.5]undecanyl; R3 is C1-C3 alkyl, C7-C3 alkenyl, phenyl optionally substituted by chloro, fluoro or C1-C3 alkoxy, phenyl(C1-C3)alkyl, ethenyl or thienyl; R4 is hydrogen, (C1-C6)alkyl, (C1-C6)alkyl substituted by amino, guanidino, (C1-C3)alkylamino, acetylamino, pyrroryl-COxe2x80x94NHxe2x80x94, pyridyl-COxe2x80x94NHxe2x80x94, heterocyclic selected from piperidino, hexamethyleneimino, morpholino, pyrrolidino, pyrrolyl, pyridinyl, pyrimidinyl and pyrimidinylpiperazino; R5 is fluoro, chloro, (C1-C3)alkyl or (C1-C3)alkoxy; and n is 0, 1 or 2.
Preferred individual compounds of this invention are following:
1-{1-[1-Methyl-1-(2-thienyl)ethyl]-4-piperidinyl}-1,3-dihydro-2H-1,3-benzimidazol-2-one, 1-[1-(1-Phenylcycloheptyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one, 1-[4-Piperidinyl-1-(1-Propylcyclononyl)]-1,3-dihydro-2H-1,3-benzimidazol-2-one, 1-[1-(1-Phenylcyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one, 1-[1-(1-Phenylcyclononyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one, 1-{1-[1-(4-Fluorophenyl)cycloheptyl]-4-piperidinyl}-1,3-dihydro-2H-1,3-benzimidazol-2-one, 1-[1-(1-Methylcyclononyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one, 1-[1-(1-Ethylcyclononyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one, 1-[1-(1-Methylcyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one, 1-[1-(1-Phenylcyclohept-4-enyl)-4-Piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, 1-(2-Aminoethyl)-3-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, 1-(6-Aminohexyl)-3-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, 1-(2-Aminoethyl)-3-[1-(1-phenylcyclohept-4-enyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-3-(2-piperidinoethyl)-1,3-dihydro-2H-benzimidazol-2-one, and a salt thereof.
The most preferred compounds are:
1-[1-(phenylcycloheptyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one, 1-[1-(1-methylcyclononyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one, 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one, 1-(6-aminohexyl)-3-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[1-(1-phenylcycloheptyl)4-piperidinyl]-3-(2-piperidinoethyl)-1,3-dihydro-2H-benzimidazol-2-one, and a salt thereof.
The present invention also relates to a pharmaceutical composition for the treatment of a disorder or condition mediated by ORL1-receptor and its endogenous ligands in a mammal, including a human, which comprises an effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The present invention also relates to a method for treating a disorder or condition, the treatment of which can be effected or facilitated by binding to ORL1-receptor in a mammal, including a human, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
The compounds of Formula (I) of this invention can be useful as an analgesic, anti-inflammatory, diuretic, anesthetic, neuroprotective, anti-hypertensive or an anti-anxiety agent, or an agent for appetite control or hearing regulation. The compounds of Formula (I) of this invention can be used as agents for the treatment of the other psychiatric, neurological and physiological disorders such as depression, trauma, memory loss due to Alzheimer""s disease or other dementias, epilepsy and convulsions, symptoms of withdrawal from drugs of addiction, control of water balance, sodium excretion, and arterial blood pressure disorders.
The following reaction Schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated, R1, R2, R3, R4, R5 and R6 in the reaction Schemes and discussion that follow are defined above.
General Synthesis
The ORL1 agonists of Formula (I) of this invention may be prepared according to the following methods.
Reaction Scheme 1 illustrates a method for the preparation of Compound (I). 
As shown in Scheme 1, Compounds (I) may be obtained from benzimidazolinylpiperidine compound (II) via intermediate (IV). First, Compound (II) may be subjected to the Strecker synthesis with the stoichiometric amount of ketone (III). Second, Compound (IV) can be subjected to Grignard reaction with a reagent represented by the formula R3MgX (X is such as halo) to give Compound (I).
The Strecker synthesis can be carried out using a suitable cyanating agent according to known procedures reported by A. Kalir, et al., (J. Med. Chem. 1969, 12, 473). Suitable cyanating agents include cyanide such as potassium cyanide (KCN). This reaction can be carried out at pH of about 3 to 11 in ice-cool water for 30 min to 7 days. The Grignard reaction can be carried out under unhydrous condition according to known procedures (e.g., O. A. Al-Deeb. Arzneim.-Forsch./Drug Res., 1994, 44, 1141). More specifically, this reaction can be carried out in a suitable solvent such as tetrahydrofuran (THF), at from about room temperature to the reflux temperature of the solvent for 30 minutes to 48 hours.
Compounds of the Formula (I) can be also prepared by the methods illustrated in Scheme 2. 
As shown in Scheme 2, Compounds (I) wherein R4 is hydrogen can be prepared through the steps comprising (a) reductive amination of a piperidine4-one (V) to give the 4-aminopiperidine (VI), (b) coupling reaction of the compound (VI) with a nitrobenzene (VII), (c) reduction of the resultant product of step (b), and (d) carbonylation reaction of the resultant product of step (c). Each reaction step is described below.
(a) The reductive amination of Compound (V) can be carried out under known conditions. For example, this reductive amination can be carried out in the presence of a reducing agent such as sodium cyanoborohydride (NaBH3CN) and ammonium acetate, in a suitable solvent such as methanol at about room temperature for about 1 hour to 2 days (U.S. Pat. No. 5,124,457). The reductive amination can also be carried out according to the procedures reported by B. de Costa et al., J. Chem. Soc., Perkin Trans. 1, 1992, 1671.
(b-d) Steps (b) through (d) can be achieved by known procedures reported for example by N. A. Meanwell et al., Bioorganic and Medicinal Chemistry Letters, 1996, 6, 1641. More specifically, the coupling reaction (b) can be carried out in the presence of potassium carbonate (K2CO3) in acetonitrile with heating. The reduction (c) can be carried out in the presence of a reducing agent such as tin (II) chloride in a polar solvent such as ethanol with heating. The carbonylation (d) can be carried out in the presence of a carbonylating agent such as carbonyldiimidazole or trichloromethyl chloroformate in a reaction inert solvent such as tetrahydrofuran (THF) with heating.
Compounds (I) wherein R4 is C1-C4 alkyl can be obtained by alkylation of Compound (I) wherein R4 is hydrogen using a desired alkylating agent. This alkylation can be carried out in the presence of a reaction inert solvent such as DMF, in the presence of strong base such as sodium hydride, at a temperature from about 0xc2x0 C. to room temperature, for 1 minute to 6 hours. Suitable alkylating agents are such as alkylhalides or mesylate.
Compounds (I) wherein R1 and R2, taken together with the carbon atom to which they are attached, form a monocyclic, bicyclic or spirocyclic ring can be prepared by subjecting an intermediate (II) to the Grignard reaction according to the similar procedures illustrated in Scheme 1. The suitable Grignard reagents are those represented by the formula of R1R2R3CMgX wherein R1 and R2, taken together with the carbon atom to which they are attached, form a monocyclic or bicyclic ring; and X is halo.
Intermediates (V) can be prepared by the methods illustrated in Scheme 3. 
Route 1 illustrates a preparation of Compound (V) from known 4-piperidinol (VIII) according to the procedures reported by A. Kalir et al., J. Med. Chem., 1969, 12, 473. First, Compound (VIII) can be condensed with Compound (III) and cyanated to give Compound (IX). Second, obtained Compound (IX) can be subjected to the Grignard reaction with R3MgX wherein X is halo to give Compound (X). Then, Compound (X) can be oxidized to give Compound (V).
Route 2 illustrates a preparation of Compound (V) from a starting amine (XI) comprising condensation of (XI) with 3,3 -ethylenedioxypentane-1,5-diol dimethanesulfonate (XII) followed by deprotection. These reactions can be carried out under known conditions (e.g., B. de Costa et al., J. Chem. Soc., Perkin Trans. I. 1992, 1671). Compound (V) can be prepared directly from a starting amine (XI) using N-ethyl-N-methyl4-oxopiperidinium iodide according to the procedure of D. M. Tschaen et al (J. Org. Chem. 1995, 60, 4324).
Route 3 illustrates a preparation of Compound (V) from a known oxygen protected piperidine-4-one (XIV). This preparation comprises (a) condensation of (XIV) with (III), (b) cyanation, (c) the Grignard reaction and (d) deprotection. These reactions can be carried out under the same conditions described in Scheme 1.
The starting amines (XI) can be readily prepared by known methods for a skilled person (e.g., J. Weinstock, et al., OS IV 910, E. J. Cone, et al., J. Med. Chem., 1981, 24, 1429, and Ritter Reaction described in Org. React., 1969, 17, 313).
Compound (II) can be prepared by known methods as illustrated in Scheme 4. 
In Scheme 4, Compound (II) can be prepared by the method comprising (a) nucleophilic substitution of (XVI) with (XVII), (b) reduction of (XVIII), (c) carbonylation, (d) alkylation of (XIX) and (e) deprotection of (IIxe2x80x2).
(a) Nucleophilic substitution of (XVI) with (XVII):
A substituted nitrobenzene (XVI) wherein L is a leaving group, can be subjected to nucleophilic substitution with an aminopiperidine (XVII) wherein Pr is a protecting group, to give the compound (XVIII). Suitable leaving groups include halo, preferably F. Suitable N-protecting groups include benzyl, benzyloxycarbonyl and tert-butyloxycarbonyl, preferably benzyl. This reaction can be carried out in the presence of a metal catalyst such as copper (II) oxide, and weak base such as potassium carbonate, at from about 100xc2x0 C. to 300xc2x0 C. for about 30 minutes to 48 hours (preferably at 150xc2x0 C. to 250xc2x0 C. for 60 minutes to 24 hours).
(b, c) Reduction and Carbonylation of (XVIII):
Compound (XVIII) can be reduced and carbonylated to give the amine (XIX). The reduction can be carried out in the presence of a reducing agent in a polar solvent. Suitable reducing agents include metal halide such as tin (II) chloride hydrate (SnCl2xe2x80x94H2O), and suitable polar solvents include alcohol such as ethanol. This reaction can be carried out at up to the reflux temperature of the reaction mixture for 30 minutes to 24 hours. The subsequent carbonylation can be carried out according to the known procedures. These procedures are reported for example by N. A. Meanwell et al., Bioorganic and Medicinal Chemistry Letters, 1996, 6, 1641 (also referred to in Scheme 2) and R. Iemura et al., Chem. Pharm. Bull., 1989, 37, 962.
(d) Alkylation of (XIX):
Compound (XIX) can be alkylated to give Compound (IIxe2x80x2) by known methods. For example, this alkylation can be carried out by reacting Compound (XIX) with a suitable alkylating agent such as alkyl halide. This reaction can be carried out in the presence of a base such as sodium hydride (NaH) in a reaction inert solvent such as dimethylformamide at about room temperature for 30 minutes to 24 hours.
(e) Deprotection of (IIxe2x80x2):
The protecting group of Compound (IIxe2x80x2) can be removed by conventional method, for example, by catalytic hydrogenation to give Compound (II). This catalytic hydrogenation can be conducted in a polar solvent such as alcohol (e.g., methanol and ethanol), under hydrogen at about room temperature, for from about 30 minutes to 48 hours. Suitable catalysts are noble metal catalysts such as palladium (II) hydroxide on carbon.
The starting materials (XVI) and (XVII) are known compounds, and can be prepared according to known procedures for a person skilled in the art.
To the 3-position of the benzimidazole ring, several functional groups (R4) can be introduced by methods known to those skilled in the art. For example, the compounds of formula (I) wherein R4 is H, can be reacted with R4xe2x80x94L (L is a leaving group such as halo or MsO) in the presence of a base such as sodium hydride(NaH) in a reaction inert solvent such as tetrahydrofuran (THF) and dimethylformamide (DMF) at about 0xc2x0 C. to 80xc2x0 C. for 20 minutes to 24 hours. When R4xe2x80x94L has a terminal amino group, it can be protected by an amino-protecting group such as tert-butoxycarbonyl during the above reaction. The amino-protecting group can be removed from the resultant product by a conventional method, for example, by treatment with hydrochloric acid in methanol. If required, the resultant terminal amino group can be further reacted with X-halo (X is heteroaryl, etc.) to attach the X group thereto. The terminal amino group can be also reacted with an acylating agent such as Xxe2x80x94COxe2x80x94Cl, Xxe2x80x94COOH, or its acid anhydride.
Unless indicated otherwise, the present pressure of each of the above reactions is not critical. Generally, the reactions will be conducted at a pressure of about one to about three atmosphere, preferably at ambient pressure (about one atmosphere).
The compounds of Formula (I) of this invention are basic, therefore they will form acid-addition salts. All such salts are within the scope of this invention. However, it is necessary to use an acid addition salts which is pharmaceutically-acceptable for administration to a mammal. The acid-addition salts can be prepared by standard methods. For example, the salts may be prepared by contacting the basic compounds with acid in substantially equivalent proportions in water or an organic solvent such as methanol or ethanol, or a mixture thereof. The salts can be isolated by crystallization from or evaporation of the solvent. Typical salts which can be formed are the hydrochloride, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, p-toluenesulfonate, oxalate and pamoate (1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphtoate)) salts.
The compounds of Formula (I) have been found to possess selective affinity for ORL1-receptors and ORL-1 receptor agonist activity. Thus, these compounds are useful as an analgesic, anti-inflammatory diuretic, anesthetic, neuroprotective, anti-hypertensive or an anti-anxiety agent, or an agent for appetite control or hearing regulation, in mammalian subjects, especially humans in need of such agents. These compounds are also useful as agents for the treatment of the other psychiatric, neurological and physiological disorders such as depression, trauma, memory loss due to Alzheimer""s disease or other dementias, epilepsy and convulsions, symptoms of withdrawal from drugs of addiction, control of water balance, sodium excretion, and arterial blood pressure disorders.
The affinity, agonist activities and analgesic activity can be demonstrated by the following tests respectively. Within the following descriptions of these tests, xe2x80x9cSPAxe2x80x9d means (xcex1,R)-N,N-dimethyl-xcex1-phenyl-benzeneethanamine hydrochloride; xe2x80x9cCHO-K1xe2x80x9d refers to Chinese Hamster Ovary cells (ATCC No. CCL-61); xe2x80x9cCI-977xe2x80x9d refers to, N-methyl-N-[(5R,7S,8S)-7-(1-pyrrolidinyl)-1-oxiaspiro[4.5]dec-8-yl]-4-benzofuranacetamide monohydrochloride; xe2x80x9cDPDPExe2x80x9d refers to [2-D-Penicillamine, 5-D-Pencilliamine]enkephalin; xe2x80x9cDAMGOxe2x80x9d refers to L-tyrosyl-D-alanylglycyl-N-(2-hydroxyethyl)-Nxcex1-methyl-L-phenylalaninamide; xe2x80x9cHEKxe2x80x9d refers to (N-2-hydroxyethylpiperazine-Nxe2x80x2-2-ethane sulfonic acid); and xe2x80x9cICRxe2x80x9d refers to a strain of mouse designated Tac:Icr:Ha(ICR) (Taconic Farms Inc., Germantown, N.Y.).
Selective Affinity for ORL1-receptors
ORL1-receptor Affinity
The ORL1 receptor binding affinity of the compounds of this invention are determined by the following procedures. Human ORL1 receptor transfected HEK-293 cell membranes and wheat-germ agglutinin coated SPA beads are combined with 0.4 nM[3H]nociceptin and unlabeled test compounds in 200 xcexcl of 50 mM Hepes buffer pH7.4 containing 10 mM MgCl2 and 1 xcexcM EDTA. This mixture is incubated at room temperature (abbreviated as rt) for 30 min to 60 min. Non specific binding is determined by the addition of 1 xcexcM nociceptin. Radioactivity is counted by Wallac 1450 MicroBeta.
xcexc-receptor Affinity
The mu (xcexc) opioid receptor binding affinity of the compounds of this invention are determined by the following procedures. Human-mu opioid receptor transfected CHO-K1 cell membranes and wheat-germ agglutinin coated SPA beads are combined with 1.0 nM[3H]DAMGO and unlabeled test compounds in 200 xcexcl of 50 mM Hepes buffer pH7.4 containing 10 mM MgCl2 and 1 mM EDTA. This mixture is incubated at rt for 30 min to 60 min. Non specific binding is determined by the addition of 1 xcexcM DAMGO. Radioactivity was counted by Wallac 1450 MicroBeta.
xcexa-receptor Affinity
The kappa (xcexa) opioid receptor binding affinity of the compounds of this invention are determined by the following procedures. Human kappa-opioid receptor transfected CHO-K1 cell membranes and wheat-germ agglutinin coated SPA beads are combined with 0.5 nM[3H]CI-977 and unlabeled test compounds in 200 xcexcl of 50 mM Hepes buffer pH7.4 containing 10 mM MgCl2 and 1 mM EDTA. This mixture is incubated at rt for 30 min to 60 min. Non specific binding is determined by the addition of 1 xcexcM CI-977. Radio activity is counted by Wallac 1450 MicroBeta.
xcex4-receptor Affinity
The delta (xcex4) opioid receptor binding affinity of the compounds of this invention are determined by the following procedures. Human delta opioid receptor transfected CHO-K1 cell membranes and wheat-germ agglutinin coated SPA beads are combined with 2.0 nM[3H]DPDPE and unlabeled test compounds in 200 xcexcl of 50 mM Hepes buffer pH7.4 containing 10 mM MgCl2 and 1 mM EDTA. The assay is incubated at room temperature for 30 min to 60 min. Non specific binding are determined by the addition of 1 xcexcM of each non-labeled ligands. Radioactivity is counted by Wallac 1450 MicroBeta.
Each percent non specific binding thus obtained is graphed as a function of compound concentration. A sigmoidal curve is used to determine IC50 values.
All compounds of Example 1 through 89 were tested by the above procedures and demonstrated good affinity for ORL1-receptors, or lower affinity for mu-receptors. In this testing, the above-mentioned preferred compounds demonstrated higher affinity for ORL1-receptors than for mu-receptors (i.e., IC50 for ORL1-receptors/IC50 for mu-receptors were less than 1.0).
Functional Assay
The functional activity of the compounds of this invention in each opioid receptor can be determined in 35S-GTPxcex3S binding system according to the procedures reported by L. J. Sim, R. Xiao and S. Childers Neuroreort Vol. 7, pp. 729-733, 1996. Each human ORL1-, mu-, kappa- and delta-receptor transfected CHO-K1 or HEK cell membranes are used. The membranes are suspended in ice-cold 20 mM HEPES buffer pH 7.4, containing 100 mM NaCl, 10 mM MgCl2 and 1 mM EDTA. 0.17 mg/ml of Dithiothreitol (DTT) is added to this buffer prior to use. Membranes are incubated at 25xc2x0 C. for 30 minutes with the appropriate concentration of test compounds in the presence of 5 xcexcM GDP, 0.4 nM of 35S-GTPxcex3S and Wheat-germ agglutinin (WGA) coated SPA bead (1.5 mg) in a 0.2 ml total volume. Basal binding is assessed in the absence of agonist, and non-specific binding is determined with 10 xcexcM GTPxcex3S. Radio activity is counted by Wallac 1450 MicroBeta.
Analgesic Tests
Tail Flick Test
Male ICR mice, 4 weeks old and weighing 19-25 g, are used. The training sessions are performed until mice can flick their tails within 4.0 sec by using Analgesia Meter MK-330A (Muromachi Kikai, Japan). Selected mice are used in this experiment. The latency time is recorded twice at 0.5, 1.0, and 2.0 h after administration of the compound. The intensity of the beam is set to 80. Cut-off time is set to 8.0 sec. A compound of this invention is subcutaneously administered 30 min before the test. The ED50 value, defined as the dose of the compounds tested which halves the tail flicking is observed in the control group.
Acetic Acid Writhing Test
Male ICR mice, 4 weeks old and weighing 21-26 g, are used. They are fasted the day before use. Acetic acid is diluted with saline to the concentration of 0.7%(v/v) and injected intraperitoneally (0.2 ml/10 g of body weight) to mice with a 26 gauge needle. A compound of this invention is dissolved in 0.1% methyl cellulose(MC)-saline and subcutaneously administered to mice 0.5 h before acetic acid injection. After the acetic acid injection, each animal is placed in a IL beaker and recorded by a video tape recorder. Number of writhing is counted from 5 to 15 min after acetic acid injection. The ED50 value, defined as the dose of the compounds tested which halves the writhing is observed in the control group. Some compounds of this invention demonstrated good analgesic activity in this test (i.e., ED50 value of 0.02 mg/kg to 1 mg/kg).
Formalin Licking Test
Male SD rats (80-100 g) are injected subcutaneously with a test compound dissolved in 0.1% methyl cellulose(MC)-saline or vehicle. After 30 min, 50 xcexcl of a 2% formalin are injected into a hind paw. The number of licking the injected paw per observation period is measured from 15 to 30 min. after the injection of formalin and expressed as % inhibition compared to the respective vehicle group. This testing method is described in, for example, (1) R. L. Follenfant, et. al., Br. J. Pharmacol. 93, 85-92 (1988); (2) H. Rogers, et al., Br. J. Pharmacol. 106, 783-789 (1992); and (3) H. Wheeler-Aceto, et al., Psychopharmacology, 104, 35-44 (1991).
The compounds of Formula (I) of this invention can be administered by conventional pharmaceutical practice via either the oral, parenteral or topical routes to mammals, for the treatment of the indicated diseases. For administration to human patient by either route, the dosage is in the range of about 0.01 mg/kg to about 3000 mg/kg body weight of the patient per day, preferably about 0.01 mg/kg to about 1000 mg/kg body weight per day, more preferably about 0.1 mg/kg to about 100 mg/kg body weight per day administered singly or as a divided dose. However, variations will necessarily occur depending upon the weight and condition of the subject being treated, compound employed, the disease state being treated and the particular route of administration chosen.
The compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers by either of the above routes previously indicated, and such administration can be carried out in single or multiple doses. Generally, the compounds can be combined with various pharmaceutically acceptable carriers in the form of tablets, powders, capsules, lozenges, trochees, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, suspensions, solutions, elixirs, syrups or the like. Such pharmaceutical carriers include solvents, excipients, coating agents, bases, binders, lubricants, disintegrants, solubilizing agents, suspending agents, emulsifying agents, stabilizers, buffering agents, tonicity agents, preservatives, flavorating agents, aromatics, coloring agents and the like.
For example, the tablets can contain various excipients such as starch, lactose, glucose, microcrystalline cellulose, calcium sulfate, calcium carbonate, talc, titanium oxide and the like, coating agents such as gelatin, hydroxypropylcellulose and the like. binding agents such as gelatin, gum arabic, methylcellulose and the like, and the disintegrating agents such as starch, agar, gelatine, sodium hydrogencarbonate and the like. Additionally, lubricating agents such as magnesium stearate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatine capsules; preferred materials in this connection also include lactose as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with diluents such as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
In general, the therapeutically-effective compounds of this invention are present in such oral dosage forms at concentration levels ranging 5% to 70% by weight, preferably 10% to 50% by weight.
The compounds of the present invention in the form of a solution may be injected parenterlly such as intradermaly, subcutaneously, intravenously or intramuscularly. For example the solutions are sterile aqueous solutions, aqueous suspensions and an edible oil solutions. The aqueous solutions may be suitably buffered (preferably pH greater than 8), and may contain enough salts or glucose to make the solution isotonic with blood. The aqueous solutions are suitable for intravenous injection purposes. The aqueous suspensions may contain a suitable dispersing or suspending agents such as sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin. The aqueous suspensions can be used for subcutaneous or intramuscular injections. The edible oil such as cottonseed oil, sesame oil, coconut oil or peanut oil can be employed for the edible oil solutions. The oil solutions are suitable for intra-articular, intramuscular and subcutaneous injection. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
It is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.